Date of Award
Doctor of Philosophy
Part I describes the successful total synthesis of the antifugal antibiotic kalafungin and a close analogue, 9-deoxykalafungin. The key step, in which all of the carbon atoms present in the target molecules were assembled, is the addition of 2-tert-butoxyfuran to either 2-acetyl-1,4-naphthoquinone or 2-acetyl-8-methoxy-1,4-naphthoquinone. Hydride reduction followed by removal of the tert-butyl protecting group and addition of the C-1 alcohol to the unmasked butenolide afforded intermediate naphthydroquinone dimethyl ethers, which were oxidized to the target molecules with argentic oxide;Part II describes the first successful total synthesis of the trichothec-9-ene skeleton containing oxygenation at both carbon-15 and in the C-ring. The four asymmetric centers present were introduced unambiguously with the correct relative configuration. The synthesis began with a Lewis acid catalyzed Diels-Alder reaction between 1-acetoxy-3-methyl butadiene and 3-hydroxymethyl-3-buten-2-one. The major product from this reaction had the desired stereochemistry at carbons 6 and 11, resulting from cis-endo addition. The thermal reaction afforded the diastereomeric acetoxyketone as the major product. The adduct from the former reaction was transformed to a bicyclic lactone by an intramolecular Knoevenagel condensation. This lactone could be converted into the desired keto-alcohol by reduction of the lactone and nitrile followed by an oxidation and Curtius degradation. Desilylation furnished an alcohol, which was reprotected as the bromoacetate. The third asymmetric center was introduced via an intramolecular alkylation of the regiodefined silyl enol ether of the ketone with the proximate haloester. The (delta)-lactone produced was transformed to an aldehyde, which underwent intramolecular aldolization to introduce the final asymmetric center. Oxidation of the resulting ketol afforded 15-tert-butyldimethyl-silyloxy-13-nortrichothec-9-ene-3,12-dione.
Digital Repository @ Iowa State University, http://lib.dr.iastate.edu/
Bruce David Roth
Roth, Bruce David, "The synthesis of antifungal antibiotics " (1981). Retrospective Theses and Dissertations. 6849.